HCV is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.
The current standard of care for HCV, which employs a combination of pegylated-interferon and ribavirin, has a non-optimal success rate in achieving sustained viral response and causes numerous side effects. Thus, there is a clear and long-felt need to develop effective therapies to address this undermet medical need.
HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5′ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome due to the high error rate of the encoded RNA dependent RNA polymerase which lacks a proof-reading capability. At least six major genotypes have been characterized, and more than 50 subtypes have been described with distribution worldwide. The clinical significance of the genetic heterogeneity of HCV has demonstrated a propensity for mutations to arise during monotherapy treatment, thus additional treatment options for use are desired. The possible modulator effect of genotypes on pathogenesis and therapy remains elusive.
The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions by both acting as a cofactor for the NS3 protease and assisting in the membrane localization of NS3 and other viral replicase components. The formation of a NS3-NS4A complex is necessary for proper protease activity resulting in increased proteolytic efficiency of the cleavage events. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV with other HCV proteins, including NS5A, in a replicase complex.
Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. In particular, compounds which are effective to inhibit the function of the NS5A protein are desired. The HCV NS5A protein is described, for example, in the following references: S. L. Tan, et al., Virology, 284:1-12 (2001); K.-J. Park, et al., J. Biol. Chem., 30711-30718 (2003); T. L. Tellinghuisen, et al., Nature, 435, 374 (2005); R. A. Love, et al., J. Virol, 83, 4395 (2009); N. Appel, et al., J. Biol. Chem., 281, 9833 (2006); L. Huang, J. Biol. Chem., 280, 36417 (2005); C. Rice, et al., WO2006093867.
The present disclosure provides compounds which selectively inhibit HCV viral replication, as characterized by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:                L is selected from —O—, —CH2CH2—, —CH═CH—, —C≡C—, —OCH2—, —CH2O—, —CH2OCH2—,        
                X is hydrogen (H) or halogen and Z is hydrogen; or        X and Z, together with the carbon atoms to which they are attached, form a five- to eight-membered aromatic or non-aromatic fused ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered ring is optionally substituted with one, two, or three substitutents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, carboxy, formyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NRaRb, (NRaRb)alkyl, (NRaRb)carbonyl, oxo, and spirocycle;        X′ is hydrogen (H) or halogen and Z′ is hydrogen; or        X′ and Z′, together with the carbon atoms to which they are attached, form a five- to eight-membered aromatic or non-aromatic fused ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered ring is optionally substituted with one, two, or three substitutents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, carboxy, formyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, (NRaRb)alkyl, (NRaRb)carbonyl, oxo, and spirocycle;        Y and Y′ are each independently —CH2—, —CH2CH2—, or —CH2O—, wherein the —CH2O— is drawn such that the oxygen atom is bound to the carbon atom substituted with Rv and Rq or Rv′ and Rq′;        Rp is hydrogen or C1 to C4 alkyl;        Rq is hydrogen, alkyl, or halo; or        Rp and Rq, together with the carbon atoms to which they are attached, form a cycloalkyl ring;        Rv is selected from hydrogen, alkyl, halo, and hydroxy; or        Rv and Rq, together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring;        Rp′ is hydrogen or C1 to C4 alkyl;        Rq′ is hydrogen, alkyl, or halo; or        Rp′ and Rq′, together with the carbon atoms to which they are attached, form a cycloalkyl ring;        Rv′ are independently selected from hydrogen, alkyl, halo, and hydroxy; or        Rv′ and Rq′, together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring;        Rw and Rw′ are independently selected from hydrogen and alkyl;        R1 is hydrogen or —C(O)Rx;        R2 is hydrogen or —C(O)Ry;        Rx and Ry are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy, and alkyl, said alkyl being substituted by one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,        wherein any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkenyl, alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, —OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and        wherein any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, —NRaRb, oxo, and —C(O)OR4;        R3 is hydrogen, alkyl, or arylalkyl;        R4 is alkyl or arylalkyl;        R5 is hydrogen, alkyl, or arylalkyl;        Ra and Rb are independently selected from hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, —C(O)R6, —C(O)OR7, —C(O)NRcRd, and (NRcRd)alkyl, or alternatively, Ra and Rb, together with the nitrogen atom to which they are attached, form a five- or six-membered ring or bridged bicyclic ring structure, wherein said five- or six-membered ring or bridged bicyclic ring structure optionally may contain one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and may contain one, two, or three substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, aryl, hydroxyl, C1 to C6 alkoxy, C1 to C4 haloalkoxy, and halogen;        R6 is alkyl;        R7 is alkyl, arylalkyl, cycloalkyl, or haloalkyl; and        Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.        
In a first embodiment of the first aspect the present disclosure provides a compound of Formula (I) further characterized by Formula (Ia):
or a pharmaceutically acceptable salt or a tautomer thereof, wherein:                X is hydrogen or chloro (Cl) and Z is hydrogen; or        X and Z, together with the carbon atoms to which they are attached, form a six-membered aromatic or non-aromatic fused ring;        X′ is hydrogen or chloro (Cl) and Z′ is hydrogen; or        X′ and Z′, together with the carbon atoms to which they are attached, form a six-membered aromatic or non-aromatic fused ring;        Y is —CH2—, —CH2CH2—, or —CH2O—, wherein the —CH2O— is drawn such that the oxygen atom is bound to the carbon atom substituted with Rv and Rq;        Rp is hydrogen or C1 to C4 alkyl;        Rq is hydrogen, alkyl, or halo; or        Rp and Rq, together with the carbon atoms to which they are attached, form a cycloalkyl ring; and        Rv is selected from hydrogen, alkyl, halo, and hydroxy; or        Rv and Rq, together with the carbon atom to which they are attached, form an ethylenyl group or a cycloalkyl ring.        
In a second embodiment of the first aspect the present disclosure provides a compound of Formula (I) further characterized by Formula (Ib):
or a pharmaceutically acceptable salt or a tautomer thereof.
In a third embodiment of the first aspect the present disclosure provides a compound of Formula (I) further characterized by Formula (Ic):
or a pharmaceutically acceptable salt or a tautomer thereof.
In a fourth embodiment of the first aspect the present disclosure provides a compound of Formula (I) further characterized by Formula (Id):
or a pharmaceutically acceptable salt or a tautomer thereof.
In a fifth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:                R1 is —C(O)Rx;        R2 is —C(O)Ry;        Rx and Ry are independently alkyl substituted by at least one —NRaRb, characterized by Formula (A):        
wherein:                m is 0 or 1;        R8 is hydrogen or alkyl;        R9 is selected from hydrogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, and alkyl optionally substituted with a substituent selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, heterobicyclyl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,        wherein any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, —OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and        wherein any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, —NRaRb, oxo, and —C(O)OR4; and        R3, R4, R5, Ra, Rb, Rc, and Rd are defined as in Formula (I).        
In a sixth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                m is 0;        R8 is hydrogen or C1 to C4 alkyl;        R9 is selected from hydrogen, C1 to C6 alkyl optionally substituted with —OR12, C3 to C6 cycloalkyl, allyl, —CH2C(O)NRcRd, (NRcRd)alkyl,        
                wherein j is 0 or 1;        k is 1, 2, or 3;        n is 0 or an integer selected from 1 through 4;        each R10 is independently hydrogen, C1 to C4 alkyl, C1 to C4 haloalkyl, halogen, nitro, —OBn, or (MeO)(OH)P(O)O—;        R11 is hydrogen, C1 to C4 alkyl, or benzyl;        R12 is hydrogen, C1 to C4 alkyl, or benzyl;        Ra is hydrogen or C1 to C4 alkyl;        Rb is C1 to C4 alkyl, C3 to C6 cycloalkyl, benzyl, 3-pyridyl, pyrimidin-5-yl, acetyl, —C(O)OR7, or —C(O)NRcRd;        R7 is C1 to C4 alkyl or C1 to C4 haloalkyl;        Rc is hydrogen or C1 to C4 alkyl; and        Rd is hydrogen, C1 to C4 alkyl, or C3 to C6 cycloalkyl.        
In a seventh embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                m is 0;        R8 is hydrogen;        R9 is phenyl optionally substituted with one up to five substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, halogen, C1 to C6 alkoxy, hydroxyl, cyano, and nitro; and        NRaRb is a heterocyclyl or heterobicyclyl group selected from:        
                wherein n is 0, 1, or 2;        each R13 is independently selected from C1 to C6 alkyl, phenyl, trifluoromethyl, halogen, hydroxyl, methoxy, and oxo; and        R14 is C1 to C6 alkyl, phenyl, benzyl, or —C(O)OR15 group, wherein R15 is C1 to C4 alkyl, phenyl, or benzyl.        
In an eighth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                m is 1;        R8 is hydrogen;        R9 is C1 to C6 alkyl, arylalkyl, or heteroarylalkyl;        Ra is hydrogen; and        Rb is —C(O)OR7, wherein R7 is C1 to C6 alkyl.        
In a ninth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                R1 is —C(O)Rx;        R2 is —C(O)Ry;        Rx and Ry are heteroaryl or heterocyclyl independently selected from:        
                wherein n is 0 or an integer selected from 1 through 4;        each R13 is independently selected from hydrogen, C1 to C6 alkyl, C1 to C4 haloalkyl, phenyl, benzyl, C1 to C6 alkoxy, C1 to C4 haloalkoxy, heterocyclyl, halogen, NRcRd, hydroxyl, cyano, and oxo, where Rc and Rd are independently hydrogen or C1 to C4 alkyl; and        R14 is hydrogen (H), C1 to C6 alkyl, benzyl, or —C(O)OR4, wherein R4 is C1 to C6 alkyl.        
In a tenth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                R1 is —C(O)Rx;        R2 is —C(O)Ry;        Rx and Ry are cycloalkyl independently selected from:        
wherein                j is 0, 1, 2, or 3;        k is 0, 1, or 2;        n is 0 or an integer selected from 1 through 4;        each R13 is independently selected from hydrogen, C1 to C6 alkyl, C1 to C4 haloalkyl, C1 to C6 alkoxy, halogen, hydroxyl, cyano, and nitro; and        Ra and Rb are each independently hydrogen, C1 to C6 alkyl, or —C(O)OR7,        wherein R7 is C1 to C6 alkyl.        
In an eleventh embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein                R1 is —C(O)Rx;        R2 is —C(O)Ry;        Rx and Ry are independently arylalkyl, wherein aryl part of said arylalkyl may optionally be substituted with (NRaRb)alkyl; and        Ra and Rb are independently hydrogen, C1 to C6 alkyl, or benzyl, or alternatively, Ra and Rb, together with the nitrogen atom to which they are attached, form a five- or six-membered ring selected from        
                 wherein R15 is hydrogen, C1 to C6 alkyl, or benzyl.        
In a twelfth embodiment of the first aspect the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 are the same and are selected from the group consisting of
wherein a squiggle bond  in the structure indicates that a stereogenic center to which the bond is attached can take either (R)- or (S)-configuration so long as chemical bonding principles are not violated.
In a thirteenth embodiment of the first aspect the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein                R1 is —C(O)Rx;        R2 is —C(O)Ry; and        Rx and Ry are both t-butoxy.        
In a fourteenth embodiment of the first aspect the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein                R1 and R2 are both hydrogen.        
In a second aspect the present disclosure provides a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:                L is selected from —O—, —CH2CH2—, —CH═CH—, —C≡C—, —OCH2—, —CH2O—, —CH2OCH2—,        
                X and X′ are independently hydrogen (H) or halogen;        Rp is hydrogen or C1 to C4 alkyl, and Rq is hydrogen, or alternatively, Rp and Rq, together with the carbon atoms to which they are attached, form a cyclopropyl ring;        Rp′ is hydrogen or C1 to C4 alkyl, and Rq′ is hydrogen, or alternatively, Rp′ and        Rq′, together with the carbon atoms to which they are attached, form a cyclopropyl ring;        R1 is hydrogen or —C(O)Rx;        R2 is hydrogen or —C(O)Ry;        Rx and Ry are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy, and alkyl, said alkyl being substituted by one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,        wherein any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, —OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and        wherein any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, —NRaRb, oxo, and —C(O)OR4;        R3 is hydrogen, alkyl, or arylalkyl;        R4 is alkyl or arylalkyl;        R5 is hydrogen, alkyl, or arylalkyl;        Ra and Rb are independently selected from hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, —C(O)R6, —C(O)OR7, —C(O)NRcRd, and (NRcRd)alkyl, or alternatively, Ra and Rb, together with the nitrogen atom to which they are attached, form a five- or six-membered ring or bridged bicyclic ring structure, wherein said five- or six-membered ring or bridged bicyclic ring structure optionally may contain one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and may contain one, two, or three substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, aryl, hydroxyl, C1 to C6 alkoxy, C1 to C4 haloalkoxy, and halogen;        R6 is alkyl;        R7 is alkyl, arylalkyl, or haloalkyl; and        Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.        
In a third aspect the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Formula (I) is defined according to any of the embodiments described above in the first aspect of the present disclosure.
In a first embodiment of the third aspect the composition further comprises at least one additional compound having anti-HCV activity.
In a second embodiment of the third aspect at least one of the additional compounds is an interferon or a ribavirin.
In a third embodiment of the third aspect the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
In a fourth embodiment of the third aspect the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one additional compound having anti-HCV activity, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
In a fifth embodiment of the third aspect the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one additional compound having anti-HCV activity, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
In a fourth aspect the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) is defined according to any of the embodiments described above in the first aspect of the present disclosure.
In a first embodiment of the fourth aspect the method further comprises administering at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In a second embodiment of the fourth aspect at least one of the additional compounds is an interferon or a ribavirin.
In a third embodiment of the fourth aspect the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
In a fourth embodiment of the fourth aspect the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
In a fifth embodiment of the fourth aspect the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional compound having anti-HCV activity prior to, after or simultaneously with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
The compounds of the present disclosure can be effective to inhibit the function of the HCV NS5A protein. In particular, the compounds of the present disclosure can be effective to inhibit the HCV 1b genotype or multiple genotypes of HCV.
Therefore, this disclosure also encompasses: (1) compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (2) a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Other aspects of the present disclosure may include suitable combinations of embodiments disclosed herein.
Yet other aspects and embodiments may be found in the description provided herein.
The description of the present disclosure herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given location.
Certain features of the structure of Formula (I) are further illustrated below:

In Formula (I), as depicted above, the “pyrrolidinyl-imidazole” moiety on the left side of the “linker” is independent from the “pyrrolidinyl-imidazole” moiety on the right side of the linker group in respect to, e.g., (1) tautomer form of imidazole ring, (2) absolute configuration of the stereogenic centers on the pyrrolidine ring, and (3) substituents on the pyrrolidine nitrogen, i.e., R1 and R2 are independent from each other, although in some circumstances they are preferably the same.
It should be understood that the depiction of a pyrrolidine moiety on the “left” side or on the “right” side is for illustration purpose only, which does not in any way limit the scope of the disclosure.
In the linker group of Formula (I), the linkage between “L” and the two benzene rings encompasses all the following combinations:
wherein the “para-para,” “para-meta,” and “meta-meta” linkages are preferred.
Likewise, in Formula (I), when L is a phenylene
group, it can link to the adjacent two benzene rings by the following manners:
wherein the “para” and “meta” arrangements are preferred, and the “para” arrangement is the more preferred.
In Formula (I), when L is a vinylene (—CH═CH—) group, it can take either trans- or cis-configuration, as depicted below:

In Formula (I), when L is a cyclopropylene
group, the two benzene substituents can be either trans- or cis- to each other, forming one of the following four configurations:

In a pyrrolidine ring of a pyrrolidinyl-imidazole moiety, the stereogenic carbon center to which the imidazole group is attached can take either (R)- or (S)-configuration as depicted below:

When a cyclopropyl ring is fused onto a pyrrolidine ring of a pyrrolidinyl-imidazole moiety, i.e., when (Rp, Rq) together is —CH2—, the CH2 group of the fused cyclopropyl ring can take either α- or β-position relative to the pyrrolidine ring, as depicted below:

Thus, this disclosure is intended to cover all possible stereoisomers even when a single stereoisomer, or no stereochemistry, is described in a structure.
In Formula (I), the linkage between a benzene ring of the linker group and an imidazole ring of a pyrrolidinyl-imidazole moiety can take place in either the C-4 or the C-5 position (see below) of the imidazole ring. As a person of ordinary skill in the art would understand, due to tautomerization of the imidazole ring, a bonding of a benzene ring to the C-4 position may be equivalent to a bonding of the benzene ring to the C-5 position, as shown in the following equation:
The sample principle also applies to substituent X or X′.
Thus, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them.
In this disclosure, a floating bond (e.g.,

or a floating substituent (e.g., —R13) on a structure indicates that the bond or substituent can attach to any available position of the structure by removal of a hydrogen from the available position. It should be understood that in a bicyclic or polycyclic ring structure, unless specifically defined otherwise, the position of a floating bond or a floating substituent does not limit the position of such bond or substituent to a specific ring. Thus, the following two substituents should be construed to be equivalent:

It should be understood that the compounds encompassed by the present disclosure are those that are suitably stable for use as pharmaceutical agent.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, for substituent)(R10)n, when n is 2, each of the two R10 groups may be the same or different.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.